The present invention provides novel compounds, novel compositions, method of their use and methods of their manufacture, such compounds generally useful pharmacologically as agents in those disease states alleviated by the alteration of mitogen activated signalling pathways in general, and in particular in the inhibition or antagonism of protein kinases, which pathologically involve aberrant cellular proliferation, such disease states including tumor growth, restenosis, atherosclerosis, and thrombosis. In particular, the present invention relates to a series of substituted oxindole compounds, which exhibit protein tyrosine kinase and protein serine/threonine kinase inhibition, and which are useful in protecting a patient undergoing chemotherapy from chemotherapy-induced alopecia.
Cell growth, differentiation, metabolism and function are extremely tightly controlled in higher eukaryotes. The ability of a cell to rapidly and appropriately respond to the array of external and internal signals it continually receives is of critical importance in maintaining a balance between these processes (Rozengurt, Current Opinion in Cell Biology 1992, 4, 161-5; Wilks, Progress in Growth Factor Research 1990, 2, 97-111). The loss of control over cellular regulation can often lead to aberrant cell function or death, often resulting in a disease state in the parent organism.
The protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes and maintaining control over cellular function (Hanks, et al., Science 1988, 241, 42-52). A partial list of such kinases includes ab1, ATK , bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie1, tie2, TRK, Yes, and Zap70.
One of the most commonly studied pathways involving kinase regulation is cellular signalling from receptors at the cell surface to the nucleus (Crews and Erikson, Cell 1993, 74, 215-7). One example of this pathway includes a cascade of kinases in which members of the Growth Factor receptor Tyrosine Kinases (such as EGF-R, PDGF-R, VEGF-R, IGF1-R, the Insulin receptor), deliver signals through phosphorylation to other kinases such as Src Tyrosine kinase, and the Raf, Mek and Erk serine/threonine kinase families (Crews and Erikson, Cell 1993, 74, 215-7; Ihle, et al., Trends in Biochemical Sciences 1994, 19, 222-7). Each of these kinases is represented by several family members (Pelech and Sanghera, Trends in Biochemical Sciences 1992, 17, 233-8) which play related, but functionally distinct roles. The loss of regulation of the growth factor signalling pathway is a frequent occurence in cancer as well as other disease states.
The signals mediated by kinases have also been shown to control growth, death and differentiation in the cell by regulating the processes of the cell cycle (Massague and Roberts, Current Opinion in Cell Biology 1995, 7, 769-72). Progression through the eukaryotic cell cycle is controlled by a family of kinases called cyclin dependent kinases (CDKs) (Myerson, et al., EMBO Journal 1992, 11, 2909-17). The regulation of CDK activation is complex, but requires the association of the CDK with a member of the cyclin family of regulatory subunits (Draetta, Trends in Cell Biology 1993, 3, 287-9; Murray and Kirschner, Nature 1989, 339, 275-80; Solomon, et al., Molecular Biology of the Cell. 1992, 3, 13-27). A further level of regulation occurs through both activating and inactivating phosphorylations of the CDK subunit (Draetta, Trends in Cell Biology 1993, 3, 287-9; Murray and Kirschner, Nature 1989, 339, 275-80; Solomon, et al., Molecular Biology of the Cell. 1992, 3, 13-27; Ducommun, et al., EMBO Journal 1991, 10, 3311-9; Gautier, et al., Nature 1989, 339, 626-9; Gould and Nurse, Nature 1989, 342, 39-45; Krek and Nigg, EMBO Journal 1991, 10, 3331-41; Solomon, et al., Cell 1990, 63, 1013-24). The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle (Pines, Trends in Biochemical Sciences 1993, 18, 195-7; Sherr, Cell 1993, 73, 1059-65). Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/CDK activities. In G1, both cyclin D/CDK4 and cyclin E/CDK2 are thought to mediate the onset of S-phase (Matsushime, et al., Molecular and Cellular Biology 1994, 14, 2066-76; Ohtsubo and Roberts, Science 1993, 259, 1908-12; Quelle, et al., Genes and Development 1993, 7, 1559-71; Resnitzky, et al., Molecular and Cellular Biology 1994, 14, 1669-79). Progression through S-phase requires the activity of cyclin A/CDK2 (Girard, et al., Cell 1991, 67, 1169-79; Pagano, et al., EMBO Journal 1992, 11, 961-71; Rosenblatt, et al., Proceedings of the National Academy of Science USA 1992, 89, 2824-8; Walker and Maller, Nature 1991, 354, 314-7; Zindy, et al., Biochemical and Biophysical Research Communications 1992, 182, 1144-54) whereas the activation of cydin A/cdc2 (CDK1) and cyclin B/cdc2 are required for the onset of metaphase (Draetta, Trends in Cell Biology 1993, 3, 287-9; Murray and Kirschner, Nature 1989, 339, 275-80; Solomon, et al., Molecular Biology of the Cell. 1992, 3, 13-27; Girard, et al., Cell 1991, 67, 1169-79; Pagano, et al., EMBO Journal 1992, 11, 961-71; Rosenblatt, et al., Proceedings of the National Academy of Science USA 1992, 89, 2824-8; Walker and Maller, Nature 1991, 354, 314-7; Zindy, et al., Biochemical and Biophysical Research Communications 1992, 182, 1144-54). It is not surprising, therefore, that the loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer. (Pines, Current Opinion in Cell Biology 1992, 4, 144-8; Lees, Current Opinion in Cell Biology 1995, 7, 773-80; Hunter and Pines, Cell 1994, 79, 573-82). The selective inhibition of CDKs is therefore an object of the present invention.
The compounds of the present invention are additionally useful in the treatment of one or more diseases afflicting mammals which are characterized by cellular proliferation in the areas of blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases. Blood vessel proliferative disorders include arthritis and restenosis. Fibrotic disorders include hepatic cirrhosis and atherosclerosis. Mesangial cell proliferative disorders include glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection and glomerulopathies. Metabolic disorders include psoriasis, diabetes mellitus, chronic wound healing, inflammation, neurodegenerative diseases, macular degeneration, and diabetic retinopathy.
Inhibitors of kinases involved in mediating or maintaining these disease states represent novel therapies for these disorders. Examples of such kinases include, but are not limited to: (1) inhibition of c-Src (Brickell, Critical Reviews in Oncogenesis 1992, 3, 401-46; Courtneidge, Seminars in Cancer Biology 1994, 5, 239-46), raf (Powis, Pharmacology and Therapeutics 1994, 62, 57-95) and the cyclin-dependent kinases (CDKs) 1, 2 and 4 in cancer (Pines, Current Opinion in Cell Biology 1992, 4, 144-8; Lees, Current Opinion in Cell Biology 1995, 7, 773-80; Hunter and Pines, Cell 1994, 79, 573-82), (2) inhibition of CDK2 or PDGF-R kinase in restenosis (Buchdunger, et al., Proceedings of the National Academy of Science USA 1995, 92, 2258-62), (3) inhibition of CDK5 and GSK3 kinases in Alzheimers (Hosoi, et al., Journal of Biochemistry (Tokyo) 1995, 117, 741-9; Aplin, et al., Journal of Neurochemistry 1996, 67, 699-707), (4) inhibition of c-Src kinase in osteoporosis (Tanaka, et al., Nature 1996, 383, 528-31), (5) inhibition of GSK-3 kinase in type-2 diabetes (Borthwick, et al., Biochemical and Biophysical Research Communications 1995, 210, 738-45); (6) inhibition of the p38 kinase in inflammation (Badger, et al., The Journal of Pharmacology and Experimental Therapeutics 1996, 279, 1453-61); (7) inhibition of VEGF-R 1-3 and TIE-1 and -2 kinases in diseases which involve angiogenesis (Shawver, et al., Drug Discovery Today 1997, 2, 50-63); (8) inhibition of UL97 kinase in viral infections (He, et al., Journal of Virology 1997, 71, 405-11); (9) inhibition of CSF-1 R kinase in bone and hematopoetic diseases (Myers, et al., Bioorganic and Medicinal Chemistry Letters 1997, 7, 421-4), and (10) inhibition of Lck kinase in autoimmune diseases and transplant rejection (Myers, et al., Bioorganic and Medicinal Chemistry Letters 1997, 7,417-20).
It is additionally possible that inhibitors of certain kinases may have utility in the treatment of diseases when the kinase is not misregulated, but is nonetheless essential for maintenance of the disease state. In this case, inhibition of the kinase activity would act either as a cure or palliative for these diseases. For example, many viruses, such as human papilloma virus, disrupt the cell cycle and drive cells into the S-phase of the cell cycle (Vousden; FASEB Journal 1993, 7, 872-9). Preventing cells from entering DNA synthesis after viral infection by inhibition of essential S-phase initiating activities such as CDK2, may disrupt the virus life cycle by preventing virus replication. This same principle may be used to protect normal cells of the body from toxicity of cycle-specific chemotherapeutic agents (Stone, et al., Cancer Research 1996, 56, 3199-202; Kohn, et al., Journal of Cellular Biochemistry 1994, 54, 440-52). Inhibition of CDKs 2 or 4 will prevent progression into the cycle in normal cells and limit the toxicity of cytotoxics which act in S-phase, G2 or mitosis. Furthermore, CDK2/cyclin E activity has also been shown to regulate NF-kB: Inhibition of CDK2 activity stimulates NF-kB-dependent gene expression, an event mediated through interactions with the p300 coactivator (Perkins, et al., Science 1997, 275, 523-7). NF-kB regulates genes involved in inflammatory responses, (such as hematopoietic growth factors chemokines and leukocyte adhesion molecules) (Baeuerle and Henkel, Annual Review of Immunology 1994, 12, 141-79) and may be involved in the suppression of apoptotic signals within the cell (Beg and Baltimore, Science 1996, 274, 782-4; Wang, et al., Science 1996, 274, 784-7; Van Antwerp, et al., Science 1996, 274, 787-9). Thus, inhibition of CDK2 may suppress apoptosis induced by cytotoxic drugs via a mechanism which involves NF-kB. This therefore suggests that inhibition of CDK2 activity may also have utility in other cases where regulation of NF-kB plays a role in etiology of disease. A further example may be taken from fungal infections: Aspergillosis is a common infection in immune-compromised patients (Armstrong, Clinical Infectious Diseases 1993, 16, 1-7). Inhibition of the Aspergillus kinases Cdc2/CDC28 or Nim A (Osmani, et al., EMBO Journal 1991, 10, 2669-79; Osmani, et al., Cell 1991, 67, 283-91) may cause arrest or death in the fungi, improving the therapeutic outcome for patients with these infections.
In brief summary, the invention comprises compounds of the formula (I): 
wherein
X is N, CH, CCF3, or C(C1-12 aliphatic);
R1 is hydrogen, C1-12 aliphatic, thiol, hydroxy, hydroxy-C1-12 aliphatic, Aryl, Aryl-C1-12 aliphatic, R6-Aryl-C1-12 aliphatic, Cyc, Cyc-C1-6 aliphatic, Het, Het-C1-12 aliphatic, C1-12 alkoxy, Aryloxy, amino, C1-12 aliphatic amino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, C1-12 alkoxycarbonyl, halogen, cyano, sulfonamide, or nitro, where R6, Aryl, Cyc and Het are as defined below;
R2 is hydrogen, C1-12 aliphatic, N-hydroxyimino-C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 aliphatic, C1-12 alkoxycarbonyl, carboxyl C1-12 aliphatic, Aryl, R6-Aryl-oxycarbonyl, R6-oxycarbonyl-Aryl, Het, aminocarbonyl, C1-12 aliphatic-aminocarbonyl, Aryl-C1-12 aliphatic-aminocarbonyl, R6-Aryl-C1-12 aliphatic-aminocarbonyl, Het-C1-12 aliphatic-aminocarbonyl, hydroxy-C1-12 aliphatic-aminocarbonyl, C1-12-alkoxy-C1-12 aliphatic-aminocarbonyl, C1-12 alkoxy-C1-12 aliphatic-amino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, halogen, hydroxy, nitro, C-1-12 aliphatic-sulfonyl, aminosulfonyl, or C1-12 aliphatic-aminosulfonyl, where Aryl and Het are as defined below;
further wherein R1 and R2 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het below, or any of said fused rings optionally substituted by C1-12 aliphatic, halogen, nitro, cyano, C1-12 alkoxy, carbonyl-C1-12 alkoxy or oxo;
R3 is hydrogen, C1-12 aliphatic, hydroxy, hydroxy C1-12 aliphatic, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, C1-12 alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Het are as defined below;
further wherein R2 and R3 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het below, or any of said fused rings optionally substituted by C1-6 aliphatic or C1-6 aliphatic-carbonyl;
with the proviso that R1, R2, and R3 cannot simultaneously be H;
R4 is sulfonic acid, C1-12 aliphatic-sulfonyl, sulfonyl-C1-12 aliphatic, C1-12 aliphatic-sulfonyl-C1-6 aliphatic, C1-6 aliphatic-amino, R7-sulfonyl, R7-sulfonyl -C1-12 aliphatic, R7-aminosulfonyl, R7-aminosulfonyl-C1-12 aliphatic, R7-sulfonylamino, R7-sulfonylamino-C1-12 aliphatic, aminosulfonylamino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl-C1-12 aliphatic, (R8)1-3-Arylamino, (R8)1-3-Arylsulfonyl, (R8)1-3-Aryl-aminosulfonyl, (R8)1-3-Aryl-sulfonylamino, Het-amino, Het-sulfonyl, Het-aminosulfonyl, aminoiminoamino, or aminoiminoaminosulfonyl, where R7, R8, Aryl and Het are as defined below;
R5 is hydrogen;
and further wherein R4 and R5 are optionally joined to form a fused ring, said ring selected from the group as defined for Het below, or any of said used rings optionally substituted by C1-12 aliphatic, oxo or dioxo;
R6 is C1-12 aliphatic, hydroxy, C1-12 alkoxy, or halogen;
R7 is hydrogen, C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 alkoxy, hydroxy-C1-12 aliphatic, carboxylic acid, C1-12 aliphatic-carbonyl, Het, Het-C1-12-aliphatic, Het-C1-12-alkoxy, di-Het-C1-12-alkoxy Aryl, Aryl-C1-12-aliphatic, Aryl-C1-12-alkoxy, Aryl-carbonyl, C1-18 alkoxyalkoxyalkoxyalkoxyaliphatic, or hydroxyl where Het and Aryl are as defined below;
R8 is hydrogen, nitro, cyano, C1-12 alkoxy, halo, carbonyl-C1-12 alkoxy or halo-C1-12 aliphatic;
Aryl is phenyl, naphthyl, phenanthryl or anthracenyl;
Cyc is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any one of which may have one or more degrees of unsaturation;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of benzimidazole, dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, isoquinoline, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline, tetrahydrofuran, tetrazine, thidiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine and triazole, with the proviso that when R2 is thiadiazine, then R4 cannot be methylsulfone;
and the pharmaceutically acceptable salts, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbamates solvates, hydrates, affinity reagents or prodrugs thereof in either crystalline or amorphous form.
A more preferred genus of compounds of the present invention includes compounds of formula (I), defined as follows: 
wherein
X is N, CH, or C(C1-6 aliphatic);
R1 is hydrogen, C1-6 aliphatic, hydroxy-C1-6 aliphatic, Aryl-C1-6 aliphatic, R6-Aryl-C1-6 aliphatic, Cyc-C1-6 aliphatic, Het-C1-6 aliphatic, C1-6 alkoxy, Aryloxy, aminocarbonyl, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, C1-6 alkoxycarbonyl, halogen, or nitro, where R6, Aryl, Cyc and Het are as defined below;
R2 is hydrogen, C1-6 aliphatic, R7-C1-6 aliphatic, C1-6alkoxy, hydroxy-C1-6 aliphatic, C1-6 alkoxycarbonyl, carboxyl C1-6 aliphatic, Aryl, R6-Aryl-oxycarbonyl, R6-oxycarbonyl-Aryl, Het, aminocarbonyl, C1-6 aliphatic-aminocarbonyl, Aryl-C1-6 aliphatic-aminocarbonyl, R6-Aryl-C1-6 aliphatic-aminocarbonyl, Het-C1-6 aliphatic-aminocarbonyl, hydroxy-C1-6 aliphatic-aminocarbonyl, C1-6-alkoxy-C1-6 aliphatic-aminocarbonyl, C1-6 alkoxy-C1-6 aliphatic-amino, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, halogen, hydroxy, nitro, sulfo, C1-6 aliphatic-sulfonyl, aminosulfonyl, C1-6 aliphatic-aminosulfonyl, or quaternary ammonium, where R7, Aryl and Het are as defined below;
further wherein R1 and R2 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het above, or any of said fused rings optionally substituted by halogen or oxo;
R3 is hydrogen, C1-6 aliphatic, hydroxy, hydroxy C1-6 aliphatic, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, C1-6 alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Het are as defined below;
further wherein R2 and R3 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het above, or any of said fused rings optionally substituted by C1-6 aliphatic or C1-6 aliphatic-carbonyl;
with the proviso that R1, R2 and R3 cannot simultaneously be H;
R4 is sulfonic acid, C1-12 aliphatic-sulfonyl, sulfonyl-C1-12 aliphatic, C1-12 aliphatic-sulfonyl-C1-6 aliphatic, C1-6 aliphatic-amino, R7-sulfonyl, R7-sulfonyl-C1-12 aliphatic, R7-aminosulfonyl, R7-aminosulfonyl-C1-12 aliphatic, R7-sulfonylamino, R7-sulfonylamino-C-1-12 aliphatic, aminosulfonylamino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl-C1-12 aliphatic, (R8)1-3-Arylamino, (R8)1-3-Arylsulfonyl, (R8)1-3-Aryl-aminosulfonyl, (R8)1-3-Aryl-sulfonylamino, Het-amino, Het-sulfonyl, Het-aminosulfonyl, aminoiminoamino, or aminoiminoaminosulfonyl, where R7, R8, Aryl and Het are as defined below;
R5 is hydrogen;
and further wherein R4 and R5 are optionally joined to form a fused ring, said ring selected from the group as defined for Het above, or any of said used rings optionally substituted by oxo or dioxo;
R6 is hydrogen, C1-6 aliphatic, hydroxy, C1-6 alkoxy, or halogen;
R7 is hydrogen, C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 alkoxy, hydroxy-C1-12 aliphatic, carboxylic acid, C1-12 aliphatic-carbonyl, Het, Het-C1-12-aliphatic, Het-C1-12-alkoxy, di-Het-C1-12-alkoxy Aryl, Aryl-C1-12-aliphatic, Aryl-C1-12-alkoxy, Aryl-carbonyl, C1-18 alkoxyalkoxyalkoxyalkoxyaliphatic, or hydroxyl where Het and Aryl are as defined below;
R8 is hydrogen or halo-C1-6 aliphatic;
Aryl is phenyl, or naphthyl;
Cyc is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any one of which may have one or more degrees of unsaturation;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of benzimidazole, dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine and triazole with the proviso that when R2 is thiadiazine, then R4 cannot be methylsulfone; and the pharmaceutically acceptable salts, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbamates, solvates, hydrates, affinity reagents or prodrugs thereof in either crystalline or amorphous form.
A highly preferred genus of compounds of the present invention includes compounds of formula (I), defined as follows: 
wherein
X is N, CH, or CCH3;
R1 is hydrogen, C1-6 aliphatic, hydroxy-C1-6 aliphatic, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, Aryl-C1-6 aliphatic, R6-Aryl-C1-6 aliphatic, Cyc-C1-6 aliphatic, Het-C1-6 aliphatic, C1-6 alkoxy, Aryloxy, aminocarbonyl, C1-6 alkoxycarbonyl, halogen, or nitro, where R6, Aryl, Cyc and Het are as defined below;
R2 is hydrogen, C1-6 aliphatic, N-hydroxyimino-C1-6 aliphatic, C1-6alkoxy, C1-6 alkoxycarbonyl, Aryl, R6-Aryloxycarbonyl, Het, aminocarbonyl, C1-6 aliphatic aminocarbonyl, Ary-C1-6 aliphatic aminocarbonyl, R6-Aryl-C1-6 aliphatic aminocarbonyl, Het-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, hydroxy-C1-6 aliphatic aminocarbonyl, C1-6-alkoxy-C1-6 aliphatic aminocarbonyl, C1-6 alkoxy-C1-6 aliphatic amino, halogen, hydroxy, nitro, C1-6 aliphatic sulfonyl, or aminosulfonyl, C1-6 aliphatic aminosulfonyl, where Aryl and Het are as defined below;
further wherein R1 and R2 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het below, or any of said fused rings optionally substituted by halogen or oxo;
R3 is hydrogen, C1-6 aliphatic, hydroxy, hydroxy C1-6 aliphatic, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl C1-6 alkoxy, Aryloxy, Het, or halogen, where Aryl and Het are as defined below;
further wherein R2 and R3 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het below, or any of said fused rings optionally substituted by C1-6 alkyl or C1-6 alkylcarbonyl;
with the proviso that R1, R2 and R3 cannot simultaneously be H;
R4 is R7-sulfonyl, R7-sulfonyl C1-6-aliphatic, C1-6 aliphatic sulfonyl-C1-6 aliphatic, R7-aminosulfonyl, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, di-C1-6 aliphatic aminosulfonyl-C1-6 aliphatic, R7-aminosulfonyl C1-6 aliphatic, aminosulfonylamino, R7-C1-6 aliphatic aminosulfonyl-C1-6 aliphatic, Aryl, Het, R8-Aryl-aminosulfonyl, Het-aminosulfonyl, or aminoiminoaminosulfonyl, where R7, R8, Aryl and Het are as defined below;
R5 is hydrogen;
and further wherein R4 and R5 are optionally joined to form a fused ring, said ring selected from the group as defined for Het below, or any of said used rings optionally substituted by oxo or dioxo;
R6 is hydroxy, C1-6 alkoxy, or halogen;
R7 is hydrogen, C1-6 aliphatic, hydroxy C1-6-alkoxy, hydroxy-C1-6 aliphatic, C1-6 aliphatic carbonyl, Aryl-carbonyl, C1-12 alkoxyalkoxyalkoxyalkoxyalkyl, hydroxyl, Aryl, Aryl-C1-6-alkoxy, Aryl-C1-6-aliphatic, Het, Het-C1-6-alkoxy, di-Het-C1-6-alkoxy, Het-C1-6-aliphatic, di-Het-C1-6-aliphatic;
R8 is trifluoromethyl;
Aryl is phenyl;
Cyc is cyclobutyl;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of benzimidazole, dihydrothiophene, dioxolane, furan, imidazole, morpholine, oxazole, pyridine, pyrrole, pyrrolidine, thiadiazole, thiazole, thiophene, and triazole, with the proviso that when R2 is thiadiazine, then R4 cannot be methylsulfone;
and the pharmaceutically acceptable salts, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbamates, solvates, hydrates, affinity reagents or prodrugs thereof in either crystalline or amorphous form.
A preferred group of compounds of the present invention with respect to the substitutions at R4 are compounds of formula (I): 
wherein
X is NH;
R1 is hydrogen, C1-12 aliphatic, thiol, hydroxy, hydroxy-C1-12 aliphatic, Aryl, Aryl-C1-12 aliphatic, R6-Aryl-C1-12 aliphatic, Cyc, Cyc-C1-6 aliphatic, Het, Het-C1-12 aliphatic, C1-12 alkoxy, Aryloxy, amino, C1-12 aliphatic amino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, C1-12 alkoxycarbonyl, halogen, cyano, sulfonamide, or nitro, where R6, Aryl, Cyc and Het are as defined below;
R2 is hydrogen, C1-12 aliphatic, N-hydroxyimino-C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 aliphatic, C1-12 alkoxycarbonyl, carboxyl C1-12 aliphatic, Aryl, R6-Ary-oxycarbonyl, R6-oxycarbonyl-Aryl, Het, aminocarbonyl, C1-12 aliphatic-aminocarbonyl, Aryl-C1-12 aliphatic-aminocarbonyl, R6-Aryl-C1-12 aliphatic-aminocarbonyl, Het-C1-12 aliphatic-aminocarbonyl, hydroxy-C1-12 aliphatic-aminocarbonyl, C1-12-alkoxy-C1-12 aliphatic-aminocarbonyl, C1-12 alkoxy-C1-12 aliphatic-amino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, halogen, hydroxy, nitro, C1-12 aliphatic-sulfonyl, aminosulfonyl, or C1-12 aliphatic-aminosulfonyl, where Aryl and Het are as defined below;
further wherein R1 and R2 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het below, or any of said fused rings optionally substituted by halogen, nitro, cyano, C1-12 alkoxy, carbonyl-C1-12 alkoxy or oxo;
R3 is hydrogen, C1-12 aliphatic, hydroxy, hydroxy C1-12 aliphatic, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, C1-12 alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Het are as defined below;
further wherein R2 and R3 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het below, or any of said fused rings optionally substituted by C1-6 aliphatic or C1-6 aliphatic-carbonyl;
with the proviso that R1, R2 and R3 cannot simultaneously be H;
R4 is R7-aminosulfonyl, R7-aminosulfonyl-C1-12 aliphatic, R7-sulfonylamino, R7-sulfonylamino-C1-12 aliphatic, aminosulfonylamino, di-C1-12 aliphatic aminosulfonyl, di-C1-12 aliphatic aminosulfonyl-C1-12 aliphatic, (R8)1-3-Aryl-aminosulfonyl,
(R8)1-3-Aryl-sulfonylamino, or aminoiminoaminosulfonyl, where R7, R8, Aryl and Het are as defined below;
R5 is hydrogen;
R6 is C1-12 aliphatic, hydroxy, C1-12 alkoxy, or halogen;
R7 is hydrogen, C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 alkoxy, hydroxy-C1-12 aliphatic, carboxylic acid, C1-12 aliphatic-carbonyl, Het, Het-C1-12-aliphatic, Het-C1-12-alkoxy, di-Het-C1-12-alkoxy Aryl, Aryl-C1-12-aliphatic, Aryl-C1-12-alkoxy, Aryl-carbonyl, C1-18 alkoxyalkoxyalkoxyalkoxyaliphatic, or hydroxyl where Het and Aryl are as defined below;
R8 is hydrogen, nitro, cyano, C1-12 alkoxy, halo, carbonyl-C1-12 alkoxy or halo-C1-12 aliphatic;
Aryl is phenyl, naphthyl, phenanthryl or anthracenyl;
Cyc is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any one of which may have one or more degrees of unsaturation;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of benzimidazole, dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine and triazole with the proviso that when R2 is thiadiazine, then R4 cannot be methylsulfone;
and the pharmaceutically acceptable salts, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbamates solvates, hydrates, affinity reagents or prodrugs thereof in either crystalline or amorphous form.
Due to the presence of an oxindole exocyclic double bond, also included in the compounds of the invention are their respective pure E and Z geometric isomers as well as mixtures of E and Z isomers. The invention as described and claimed does not set any limiting ratios on prevalence of Z to E isomers. Thus compound number 104 in the tables below is disclosed and claimed as the E geometric thereof, the Z geometric isomer thereof and a mixture of the E and Z geometric isomers thereof, but not limited by any given ratio(s).
Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula.
Certain of the compounds as described will contain one or more chiral, or asymmetric, centers and will therefore be capable of existing as optical isomers that are either dextrorotatory or levorotatory. Also included in the compounds of the invention are the respective dextrorotatory or levorotatory pure preparations, and mixtures thereof.
Certain compounds of formula (I) above may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
The present invention also provides compound of formula (I) and pharmaceutically acceptable salts thereof (hereafter identified as the xe2x80x98active compoundsxe2x80x99) for use in medical therapy, and particularly in the treatment of disorders mediated by CDK2 activity, such as alopecia induced by cancer chemotherapy.
A further aspect of the invention provides a method of treatment of the human or animal body suffering from a disorder mediated by a mitogen activated protein kinase which comprises administering an effective amount of an active compound of formula (I) to the human or animal patient.
Another aspect of the present invention provides the use of an active compound of formula (I), in the preparation of a medicament for the treatment of malignant tumors, or for the treatment of alopecia induced by cancer chemotherapy or induced by radiation therapy. Alternatively, compounds of formula (I) can be used in the preparation of a medicament for the treatment of a disease mediated by a kinase selected from the group consisting of ab1, ATK, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros ,tie1, tie2, TRK, Yes, and Zap70. Additionally, compounds of formula (I) can be used in the preparation of a medicament for the treatment of organ transplant rejection, of inhibiting tumor growth, of treating chemotherapy-induced alopecia, chemotherapy-induced thrombocytopenia or chemotherapy-induced leukopenia, or of treating a disease state selected from the group consisting of mucocitis, restenosis, atherosclerosis, rheumatoid arthritis, angiogenesis, hepatic cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, a glomerulopathy, psoriasis, diabetes mellitus, inflammation, a neurodegenerative disease, macular degeneration, actinic keratosis and hyperproliferative disorders.
Another aspect of the present invention provides the use of an active compound of formula (I), in coadministration with previously known anti-tumor therapies for more effective treatment of such tumors.
Another aspect of the present invention provides the use of an active compound of formula (I) in the preparation of a medicament for the treatment of viral or eukaryotic infections.
Other aspects of the present invention related to the inhibition-of mitogen-activated protein kinases are discussed in more detail below.
Compounds we have synthesized as part of the present invention which are currently preferred are listed in Tables 1 and 2 below. Compounds are identified by the numbers shown in the first column; variables below in the rest of the columns are with reference to the generic structure (I). Corresponding IUPAC nomenclature are disclosed in Table 2. Since all substituents at each point of substitution are capable of independent synthesis of each other, the tables are to be read as a matrix in which any combination of substituents is within the scope of the disclosure and claims of the invention. 
Standard accepted nomenclature corresponding to the Examples set forth in this specification are set forth below. In some cases nomenclature is given for one or more possible isomers.
Example 1: 4-[Nxe2x80x2-(4-Nitro-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z isomer).
Example 2: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-4-carboxylic acid amide (E isomer).
Example 3: 4-[Nxe2x80x2-(4-Isopropyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z isomer).
Example 4: 4-[(4-Hydroxymethyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-N-methyl-benzenesulfonamide (Z-isomer).
Example 5: 4-{Nxe2x80x2-[2-Oxo-4-(2-pyridin-4-yl-ethyl)-1,2-dihydro-indol-3-ylidene]-hydrazino}-benzenesulfonamide (Z isomer).
Example 6: 2-Oxo-3-(4-sulfamoyl-phenylamino-methylene)-2,3-dihydro-1H-indole-4-carboxylic acid ethyl ester (Z-isomer).
Example 7: 4-[Nxe2x80x2-(4-Iodo-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z isomer).
Example 8: 4-[Nxe2x80x2-(4-Isobutyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 9: 4-{Nxe2x80x2-[4-(2-Methyl-propenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}-benzenesulfonamide (Z-isomer).
Example 10: 4-{Nxe2x80x2-[4-(2-Methyl-1-butenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]hydrazino}-benzenesulfonamide and 4-{Nxe2x80x2-[4-(2-methyl-2-butenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}-benzenesulfonamide (Z-isomer).
Example 11: 4-{Nxe2x80x2-[4-(2-methylbutyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}-benzenesulfonamide (Z-isomer).
Example 12: 4-[Nxe2x80x2-(4-Cyclobutylmethyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z isomer).
Example 13: 4-[Nxe2x80x2-(4-Cyclobutylidenemethyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z isomer).
Example 14: 4-(Nxe2x80x2-{4-[2-(4-Hydroxyphenyl)-ethyl]-2-oxo-1,2-dihydro-indol-3-ylidene}-hydrazino)-benznensulfonamide (Z-isomer).
Example 15: 4-(Nxe2x80x2-{4-[2-(4-Hydroxyphenyl)-vinyll]-2-oxo-1,2-dihydro-indol-3-ylidene}-hydrazino)-benznensulfonamide (Z isomer).
Example 16: 4-[Nxe2x80x2-(2-Oxo-4-phenoxy-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (mixture of E and Z isomers).
Example 17: 4-[Nxe2x80x2-(4-Isopropoxy-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 18: 4-{Nxe2x80x2-[2-Oxo-4-(1H-pyrazol-3-yl)-1,2-dihydro-indol-3-ylidene]-hydrazino}-benzenesulfonamide (Z-isomer).
Example 19: 4-[(5-Oxazol-5-yl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]benzenesulfonamide (Z-isomer).
Example 20: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazone]-2,3-dihydro-1H-indole-5-carboxylic acid 2,3,4,5,6-pentafluorophenyl ester (Z-isomer).
Example 21: 4-[Nxe2x80x2-(5-Nitro-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z isomer).
Example 22: 4-[Nxe2x80x2-(5-Hydroxy-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z isomer).
Example 23: 4-[Nxe2x80x2-(5-Methyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (E isomer).
Example 24: N-Methyl-4-[Nxe2x80x2-(2-oxo-5-[1,2,4]triazol-1-yl-1,2-dihydro-indol-3-ylidene)hydrazino]-benzenesulfonamide (Z isomer).
Example 25: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-sulfonic acid sodium salt (Z-isomer).
Example 26: 3-[(4-Methylsulfamoyl-phenyl)hydrazono]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid amide (Z-isomer).
Example 27: 2-Oxo-3-(4-sulfamoyl-phenylamino-methylene)-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester (Z-isomer).
Example 28: 5-Bromo-3-[(4-Methylsulfonyl-phenyl)-hydrazono]-1,3-dihydro-indol-2-one (Z-isomer).
Example 29: 3-(3H-benzotriazol-5-ylamino-methylene)-5-iodo-1,3-dihydro-indol-2-one (Z-isomer).
Example 30: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-sulfonic acid amide (Z-isomer).
Example 31: 4-[Nxe2x80x2-(5-Methylsulfonyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 32: 3-[(4-Methylsulfamoyl-phenyl)-hydrazono]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (Z-isomer).
Example 33: 4-{Nxe2x80x2-[5-(1-Hydroxyimino-ethyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}-N-methyl-benzenesulfonamide (Z-isomer).
Example 34: 4-[1-(5-Oxazol-5-yl-2-oxo-1,2-dihydro-indol-3-ylidene)-ethylamino]-benzenesulfonamide (Z-isomer).
Example 35: N,N-Dimethyl-4-[(5-oxazol-5-yl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide (Z-isomer).
Example 36: 4-[1-(5-Oxazol-5-yl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (mixture of E and Z isomers).
Example 37: 4-[(2-Oxo-5-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide (Z-isomer).
Example 38: 2-Oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide (Z-isomer).
Example 39: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indol-5-carboxylic acid (furan-2-ylmethyl)-amide (Z-isomer).
Example 40: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indol-5-carboxylic acid -2,6-dimethoxy-benzylamide (Z-isomer).
Example 41: 2-Oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid(2-morpholin-4-yl-ethyl)-amide (Z-isomer).
Example 42: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid (2-imidazol-1-yl-ethyl)-amide (Z-isomer).
Example 43: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid (3-imidazol-1-yl-propyl)-amide (Z-isomer).
Example 44: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid (2-methoxyethyl)-amide (Z-isomer).
Example 45: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2-3-dihydro-1H-indole-5-carboxylic acid (2-hydroxyethyl)-amide (Z-isomer).
Example 46: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid (3-hydroxypropyl)-amide (Z-isomer).
Example 47: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid (3-hydroxy-2,2-dimethylpropyl)-amide (Z-isomer).
Example 48: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid (pyridin-3-ylmethyl)-amide (Z-isomer).
Example 49: 2-Oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid (pyridin-4-ylmethyl)-amide (Z-isomer).
Example 50: 4-[Nxe2x80x2-(5-Methoxy-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 51: 4-[Nxe2x80x2-(5-Amino-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide hydrochloride (Z-isomer).
Example 52: 4-[Nxe2x80x2-(6-Ethyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z isomer).
Example 53: 4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzensulfonic-acid-phenyl-ester (Z-isomer).
Example 54: N-{4-[(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}sulfamide (Z-isomer).
Example 55: 4-[(6-Hydroxymethyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-benzenesulfonamide (Z-isomer).
Example 56: 4-[Nxe2x80x2-(6-Bromo-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 57: 4-[Nxe2x80x2-(2-Oxo-6-phenoxy-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 58: 4-[Nxe2x80x2-(6-Ethoxy-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 59: N-[2-(2-Hydroxyethoxy)ethyl]-4-[7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacene-8-ylidenemethyl)-amino]benzenesulfonamide (Z-isomer).
Example 60: N-[2-(2-Hydroxyethyl]-4-[7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacene-8-ylidenemethyl)-amino]benzenesulfonamide (Z-isomer).
Example 61: N-Methyl-4-[Nxe2x80x2-(4-methyl-5-nitro-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 62: 4-[Nxe2x80x2-(7-Oxo-6,7-dihydro-3H-pyrrolo[3,2-e]indazol-8-ylidene)-hydrazino]-benzenesulfonamide (Z isomer).
Example 63: 4-[Nxe2x80x2-(7-Oxo-6,7-dihydro-1H-pyrrolo[2,3-g]indazol-8-ylidene)-hydrazino]-benzenesulfonamide (mixture of E and Z isomers).
Example 64: 4-[Nxe2x80x2-(7-Oxo-6,7-dihydro-3H-1,2,3,6-tetraaza-as-indacen-8-ylidene)-hydrazino]-benzenesulfonamide (mixture of E and Z isomers).
Example 65: 4-[Nxe2x80x2-(1-Chloro-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-e]indazol-8-ylidene)-hydrazino]-benzenesulfonamide (Z isomer).
Example 66: 4-[Nxe2x80x2-(1,7-Dioxo-2,3,6,7-tetrahydro-1H-2,6-diaza-as-indacen-8-ylidene)-hydrazino]-N-methyl-benzenesulfonamide (Z-isomer).
Example 67: N-(3-Hydroxy-2,2-dimethyl-propyl)-C-{4-[(7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-phenyl}-methanesulfonamide (Z-isomer).
Example 68: N-Methyl-C-{4-[Nxe2x80x2-(2-oxo-2,3-dihydro-pyrrolo[3,2-f]quinolin-1-ylidene)-hydrazino]-phenyl}-methanesulfonamide (Z-isomer).
Example 69: N-(1H-Indazol-6-yl)-4-[(7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-benzenesulfonamide (Z-isomer).
Example 70: 4-[(7-Oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-N-thiazol-2-yl-benzenesulfonamide (Z-isomer).
Example 71: N-(Amino-imino-methyl)-4-[(7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-benzenesulfonamide (Z-isomer).
Example 72: 4-[(7-Oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-N-pyridin-2-yl-benzenesulfonamide (Z-isomer).
Example 73: 8-[(2,2-Dioxo-1,3-dihydro-benzo[c]thiophen-5-ylamino-methylene)-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one (Z-isomer).
Example 74: {4-[(7-Oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-phenyl}-methanesulfonamide (Z-isomer).
Example 75: N-Allyl-C-{4-[(7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-phenyl}-methanesulfonamide (Z-isomer).
Example 76: 8-(4-Methylsulfonylmethyl-phenylamino-methylene)-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one (Z-isomer).
Example 77: N-(3-Hydroxy-2,2-dimethyl-propyl)-4-[(7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-benzenesulfonamide (Z-isomer).
Example 78: 4-[(7-Oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzenesulfonamide (Z-isomer).
Example 79: 4-[(7-Oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-N-pyrimidin-2-yl-benzenesulfonamide (Z-isomer).
Example 80: N-(5-Methyl-[1,3,4]thiadiazol-2-yl)-4-(7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-benzenesulfonamide (Z-isomer).
Example 81: N-Acetyl-4-[(7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-benzenesulfonamide (Z-isomer).
Example 82: N-Benzoyl-4-[(7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-benzenesulfonamide (Z-isomer).
Example 83: N-Methyl-4-[Nxe2x80x2(7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 84: N-[2-(2-Hydroxy-ethoxy)-ethyl]-N-methyl-4-[(7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-benzenesulfonamide (Z-isomer).
Example 85: N-(2-{2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethoxy}-ethyl)-4-[(7-oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)-amino]-benzenesulfonamide (Z-isomer).
Example 86: 4-[Nxe2x80x2-(5,6-Dimethyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z isomer).
Example 87: N-{6-Hydroxy-3-[(4-methylsulfamoylmethyl-phenyl)-hydrazono]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide (Z isomer).
Example 88: 4-[Nxe2x80x2-(6-Chloro-5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]benzene-sulfonamide (Z-isomer).
Example 89: 4-[Nxe2x80x2-(5-Hydroxy-6-isopropyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 90: 4-[Nxe2x80x2-(2-Methyl-6-oxo-5,6-dihydro-3-oxa-1,5-diaza-s-indacen-7-ylidene)-hydrazino]-benzenesulfonamide (Z isomer).
Example 91: 4-[Nxe2x80x2-(5-Acetyl-2-oxo-2,5,6,7-tetrahydro-1H-pyrrolo[2,3-f]indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 92: 4-[Nxe2x80x2-(6-Oxo-5,6-dihydro-[1,3]-dioxolo[4,5-f]indol-7-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 93: 4-[Nxe2x80x2-(2-Oxo-2,5,6,7-tetrahydro-1H-pyrrolo[2,3-f]indol-3-ylidene)-hydrazino]-benzenesulfonamide hydrobromide (Z-isomer).
Example 94: C-{4-[Nxe2x80x2-(4,6-Dichloro-5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-phenyl}-N-methyl-methanesulfonamide (Z isomer).
Example 95: 4-[Nxe2x80x2-(4-Chloro-5-hydroxy-6-methyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 96: 4-[Nxe2x80x2-(5-Hydroxy-4,6-dimethyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-benzenesulfonamide (Z-isomer).
Example 97: 3-(1H-Indazol-5-ylamino-methylene)-1,3-dihydro-indol-2-one (Z-isomer).
Example 98: 3-[(1H-Indazol-6-yl)-hydrazone]-1,3-dihydro-indol-2-one (Z-isomer).
Example 99: 4-[Nxe2x80x2-(5-Hydroxy-4,6-dimethyl-2-oxo-1,2-dihydro-indol-3-ylidene[-hydrazino]-phenyl}-N-methyl-methanesulfonamide (Z isomer).
Example 100: N-Methyl-4-(5-oxazol-5-yl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenylmethanesulfonamide (Z-isomer).
Example 101: 8-(3H-Benzotriazol-5-ylaminomethylene)-6,8-dihydro-1-thia-3,6-diaza-as-indacene-7-one (Z-isomer).
Example 102: 4-[Nxe2x80x2-2-Oxo-2,3-dihydropyrrolo[3,2-f]quinolin-1-ylidene)hydrazino]-benzenesulfonamide (Z-isomer).
Example 103: 2-Oxo-3-(4-sulfamoyl-phenylamino-methylene)-2,3dihydro-1H-indole-5-carboxylic acid isobutyl ester (Z-isomer).
Example 104: 4-[(7-Oxo-6,7-dihydro-1-thia-3,6-diaza-as-indacen-8-ylidenemethyl)amino]-N-pyridinyl4-yl-methyl benzenesulfonamide (Z-isomer).
The invention discloses six different points of substitution on structural formula (I). Each of these points of substitution bears a substituent whose selection and synthesis as part of this invention was independent of all other points of substitution on formula (I). Thus, each point of substitution is now further described individually.
Preferred substitutions at the R1 position include hydrogen, halogen, amide, nitro, lower alkyl, hydroxy, hydroxyalkyl, pyrimidineloweralkyl, loweralkoxycarbonyl, cyclic loweralkyl, hydroxyphenylloweralkyl, phenoxy, alkoxy, or pyrazole, or are fused with R2 to form fused thiazole, pyrazole, triazole, halogen-substituted diazole, acyl substituted pyrrole, and pyridine, rings. Most preferred are hydrogen, methyl and fused with R2 for form fused thiazole and fused pyridine. Most highly preferred are to be fused with R2 to form fused thiazole.
Preferred substitutions at the R2 position include hydrogen, halogen, sulfate, amine, quaternary amine, amide, ester, phenyl, alkoxy, aminosulfonyl, lower alkyl sulfonyl, furanyl lower alkyl amide, pyridinyl lower alkyl amide, alkoxy-substituted phenyl lower alkyl amide, morpholino lower alkyl amide, imidazolyl lower alkyl amide, hydroxy lower alkyl amide, alkoxy lower alkyl amide, lower alkyl amide, lower alkyl sulfonamide, lower alkyl hydroxy substituted amino, nitro, halogen-substituted phenoxycarbonyl, or triazole or oxazole rings, or are fused with R3 to form a fused oxazole, pyrrole, or dioxolane ring, which fused rings can be substituted by lower alkyl, lower alkyl carbonyl, or, when said fused ring is a hetero ring having nitrogen as the heteroatom, forming a quaternary ammonium salt ionically bonded with a halogen atom. Most preferred are hydrogen, hydroxyl, oxazolyl, or fused with R1 to form fused thiazolyl or fused pyridyl Most highly preferred are to be fused with R1 to form fused thiazole.
Preferred substitutions at R3 include hydrogen, lower alkyl, hydroxy lower alkyl, halogen, phenoxy, and alkoxy. Most preferred are hydrogen and methyl. Most highly preferred is hydrogen.
Preferred substitutions at R4 include sulfonylamino, sulfonylaminoamino, lower alkyl sulfonylamino, lower alkylsulfonyl lower alkyl, alkoxysulfonylamino, phenylcarbonylsulfonylamino, phenoxysulfonyl, hydroxy lower alkylsulfonylamino, hydroxy lower alkylsulfonylamino lower alkyl, alkyl, phenylsulfonylamino, optionally substituted by halogen substituted lower alkyl, aminoiminosulfonylamino, alkylsulfonylaminoalkyl, pyridinyl lower alkyl sulfonylamino, benzamideazolesulfonylamino, pyridylsulfonylamino, pyrimidinylsulfonylamino, thiadiazolylsulfonylamino optionally substituted by lower alkyl, thiazolesulfonylamino, hydroxyalkoxyalkylsulfonylamino, or the group 4xe2x80x2-SO2NH[(CH2)2O]4CH3, or are fused with R5 to form a fused imidazole, triazole, cyclic sulfonylamino or thiaphene ring optionally disubstituted on the sulfur heteroatom by oxo. The most preferred substitutions are 2 pyridine sulfonylamino, 4 pyridine sulfonylamino, hydroxy n-butyl sulfonylamino, methylsulfonylaminomethylene, sulfonyldimethylamino, fused 1,2,3-triazole, and sulfonylamino. Most highly preferred is 2 pyridine sulfonylamino, 4 pyridine sulfonylamino and hydroxy n-butyl sulfonylamino.
The preferred substitution at R5 is hydrogen.
Preferred substitutions at X include N, CH, and CCH3. Most preferred is NH.
Preferred individual compounds of the present invention include any one of the following compounds: 
Highly preferred compounds include 
Salts encompassed within the term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. Representative salts include the following salts: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Diethanolamine, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Metaphosphoric, Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Trifluoroacetate, Triethiodide, Trimethylammonium and Valerate.
Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of formula (I) and these form a further aspect of the invention.
Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I) above as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by formula above as mixtures with isomers thereof in which one or more chiral asymmetric centers are inverted.
As used herein, the term xe2x80x9caliphaticxe2x80x9d refers to the terms alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene.
As used herein, the term xe2x80x9clowerxe2x80x9d refers to a group having between one and six carbons.
As used herein, the term xe2x80x9calkylxe2x80x9d refers to a straight or branched chain hydrocarbon-having from one to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of xe2x80x9calkylxe2x80x9d as used herein include, but are not limited to, n-butyl, n-pentyl, isobutyl, and isopropyl, and the like.
As used herein, the term xe2x80x9calkylenexe2x80x9d refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of xe2x80x9calkylenexe2x80x9d as used herein include, but are not limited to, methylene, ethylene, and the like.
As used herein, the term xe2x80x9calkenylxe2x80x9d refers to a hydrocarbon radical having from two to ten carbons and at least one carbon-carbon double bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
As used herein, the term xe2x80x9calkenylenexe2x80x9d refers to an straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon-carbon double bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of xe2x80x9calkenylenexe2x80x9d as used herein include, but are not limited to, ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the like.
As used herein, the term xe2x80x9calkynylxe2x80x9d refers to a hydrocarbon radical having from two to ten carbons and at least one carbon-carbon triple bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed.
As used herein, the term xe2x80x9calkynylenexe2x80x9d refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon-carbon triple bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of xe2x80x9calkynylenexe2x80x9d as used herein include, but are not limited to, ethyne-1,2-diyl, propyne-1,3-diyl, and the like.
As used herein, the term xe2x80x9ccycloaliphaticxe2x80x9d refers to the terms cycloalkyl, cycloalkylene, cycloalkenyl, cycloalkenylene, cycloalkynyl and cycloalkyinylene.
As used herein, xe2x80x9ccycloalkylxe2x80x9d refers to a alicyclic hydrocarbon group with one or more degrees of unsaturation, having from three to twelve carton atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. xe2x80x9cCycloalkylxe2x80x9d includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the like.
As used herein, the term xe2x80x9ccycloalkylenexe2x80x9d refers to an non-aromatic alicyclic divalent hydrocarbon radical having from three to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of xe2x80x9ccycloalkylenexe2x80x9d as used herein include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cydopentyl-1,3-diyl, cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.
As used herein, the term xe2x80x9ccycloalkenylxe2x80x9d refers to a substituted alicyclic hydrocarbon radical having from three to twelve carbon atoms and at least one carbon-carbon double bond in the ring system, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of xe2x80x9ccycloalkenylenexe2x80x9d as used herein include, but are not limited to, 1-cyclopentene-3-yl, 1-cyclohexene-3-yl, 1-cycloheptene4-yl, and the like.
As used herein, the term xe2x80x9ccycloalkenylenexe2x80x9d refers to a substituted alicyclic divalent hydrocarbon radical having from three to twelve carbon atoms and at least one carbon-carbon double bond in the ring system, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of xe2x80x9ccycloalkenylenexe2x80x9d as used herein include, but are not limited to, 4,5-cyclopentene-1,3-diyl, 3,4-cyclohexene-1,1-diyl, and the like.
As used herein, the term xe2x80x9cheteroatom ring systemxe2x80x9d refers to the terms heterocyclic, heterocyclyl, heteroaryl, and heteroarylene. Non-limiting examples of such heteroatom ring systems are recited in the Summary of the Invention, above.
As used herein, the term xe2x80x9cheterocyclicxe2x80x9d or the term xe2x80x9cheterocyclylxe2x80x9d refers to a three to twelve-membered heterocyclic ring having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, SO2, O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more of another xe2x80x9cheterocyclicxe2x80x9d ring(s) or cycloalkyl ring(s). Examples of xe2x80x9cheterocyclicxe2x80x9d include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
As used herein, the term xe2x80x9cheterocyclylenexe2x80x9d refers to a three to twelve-membered heterocyclic ring diradical having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO2, O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more benzene rings or to one or more of another xe2x80x9cheterocyclicxe2x80x9d rings or cycloalkyl rings. Examples of xe2x80x9cheterocyclylenexe2x80x9d include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, and the like.
As used herein, the term xe2x80x9carylxe2x80x9d refers to a benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings to form anthracene, phenanthrene, or napthalene ring systems, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed. Examples of aryl include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, and the like.
As used herein, the term xe2x80x9carylenexe2x80x9d refers to a benzene ring diradical or to a benzene ring system diradical fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed. Examples of xe2x80x9carylenexe2x80x9d include, but are not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, anthracene-1,4-diyl, and the like.
As used herein, the term xe2x80x9cheteroaryxe2x80x9d refers to a five- to seven-membered aromatic ring, or to a polycyclic heterocyclic aromatic ring, containing one or more nitrogen, oxygen, or sulfur heteroatoms at any position, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed. For polycyclic aromatic ring systems, one or more of the rings may contain one or more heteroatoms. Examples of xe2x80x9cheteroarylxe2x80x9d used herein are furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, and indazole, and the like.
As used herein, the term xe2x80x9cheteroarylenexe2x80x9d refers to a five- to seven-membered aromatic ring diradical, or to a polycyclic heterocyclic aromatic ring diradical, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed. For polycyclic aromatic ring system diradicals, one or more of the rings may contain one or more heteroatoms. Examples of xe2x80x9cheteroarylenexe2x80x9d used herein are furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the like.
As used herein, the term xe2x80x9calkoxyxe2x80x9d refers to the group RaOxe2x80x94, where Ra is aliphatic.
As used herein, the term xe2x80x9calkylsulfanylxe2x80x9d refers to the group RaSxe2x80x94, where Ra is aliphatic.
As used herein, the term xe2x80x9calkylsulfenylxe2x80x9d refers to the group RaS(O)xe2x80x94, where Ra is aliphatic.
As used herein, the term xe2x80x9calalkylsulfonylxe2x80x9d refers to the group RaSO2xe2x80x94, where Ra is aliphatic.
As used herein, the term xe2x80x9cacylxe2x80x9d refers to the group RaC(O)xe2x80x94, where Ra is aliphatic, cycloaliphatic, or heterocyclyl.
As used herein, the term xe2x80x9caroylxe2x80x9d refers to the group RaC(O)xe2x80x94, where Ra is aryl.
As used herein, the term xe2x80x9cheteroaroylxe2x80x9d refers to the group RaC(O)xe2x80x94, where Ra is heteroaryl.
As used herein, the term xe2x80x9calkoxycarbonylxe2x80x9d refers to the group RaOC(O)xe2x80x94, where Ra is aliphatic.
As used herein, the term xe2x80x9cacyloxyxe2x80x9d refers to the group RaC(O)Oxe2x80x94, where Ra is aliphatic, cycloaliphatic, or heterocyclyl.
As used herein, the term xe2x80x9caroyloxyxe2x80x9d refers to the group RaC(O)Oxe2x80x94, where Ra is aryl.
As used herein, the term xe2x80x9cheteroaroyloxyxe2x80x9d refers to the group RaC(O)Oxe2x80x94, where Ra is heteroaryl.
As used herein, the term xe2x80x9coptionallyxe2x80x9d means that the subsequently described event(s) may or may not occur, and includes both conditions.
As used herein, the term xe2x80x9csubstitutedxe2x80x9d refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed.
As used herein, the terms xe2x80x9ccontainxe2x80x9d or xe2x80x9ccontainingxe2x80x9d can refer to in-line substitutions at any position along the above-defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one or more of any of O, S, SO, SO2, N, or N-alkyl, including, for example, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94SO2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94CH3 and so forth.
As used herein, the term xe2x80x9csolvatexe2x80x9d is a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I)) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol, or acetic acid.
As used herein, the terms xe2x80x9cbiohydrolyzable carbonatexe2x80x9d, xe2x80x9cbiohydrolyzable ureidexe2x80x9d and xe2x80x9cbiohydrolyzable carbamatexe2x80x9d is a carbonate, ureide, or carbamate, respectively of a drug substance (in this invention, a compound of general formula (I) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable carbamate is orally absorbed from the gut and is transformed to (I) in plasma. Many examples of such are known in the art and include by way of, example lower alkyl carbamates.
As used herein, the term xe2x80x9cbiohydrolyzable esterxe2x80x9d is an ester of a drug substance (in this invention, a compound of general formula (I) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable ester is orally absorbed from the gut and is transformed to (I) in plasma. Many examples of such are known in the art and include by way of example lower alkyl esters, lower acyloxy-alkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
As used herein, the term xe2x80x9cbiohydrolyzable amidexe2x80x9d is an amide of a drug substance (in this invention, a compound of general formula (I) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable amide is orally absorbed from the gut and is transformed to (I) in plasma. Many examples of such are known in the art and include by way of example lower alkyl amides, xcex1-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
As used herein, the term xe2x80x9cprodrugxe2x80x9d includes biohydrolyzable amides, biohydrolyzable esters and biohydrolyzable carbamates and also encompasses a) compounds in which the biohydrolyzable functionality in such a prodrug is encompassed in the compound of formula (I): for example, a lactam formed by a carboxylic group in R1 and an amine in R2, and compounds which may be oxidized or reduced biologically at a given functional group to yield drug substances of formula (I). Examples of these functional groups are, but are not limited to, 1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, and the like.
As used herein, the term xe2x80x9caffinity reagentxe2x80x9d is a group attached to the compound of formula (I) which does not affect its in vitro biological activity, allowing the compound to bind to a target, yet such a group binds strongly to a third component allowing a) characterization of the target as to localization within a cell or other organism component, perhaps by visualization by fluorescence or radiography, or b) facile separation of the target from an unknown mixture of targets, whether proteinaceous or not proteinaceous. An example of an affinity reagent according to b) would be biotin either directly attached to (I) or linked with a spacer of one to 50 atoms selected from the group consisting of C, H, O, N, S, or P in any combination. An example of an affinity reagent according to a) above would be fluorescein, either directly attached to (I) or linked with a spacer of one to 50 atoms selected from the group consisting of C, H, O, N, S, or P in any combination.
The term xe2x80x9cpharmacologically effective amountxe2x80x9d shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
Whenever the terms xe2x80x9caliphaticxe2x80x9d or xe2x80x9carylxe2x80x9d or either of their prefixes appear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall be interpreted as including those limitations given above for xe2x80x9caliphaticxe2x80x9d and xe2x80x9carylxe2x80x9d. Aliphatic or cycloalkyl substituents shall be recognized as being term equivalents to those having one or more degrees of unsaturation. Designated numbers of carbon atoms (e.g. C1-10) shall refer independently to the number of carbon atoms in an aliphatic or cyclic aliphatic moiety or to the aliphatic portion of a larger substituent in which the term xe2x80x9caliphaticxe2x80x9d appears as a prefix (e.g. xe2x80x9cal-xe2x80x9d).
As used herein, the term xe2x80x9cdisubstituted aminexe2x80x9d or xe2x80x9cdisubstituted amino-xe2x80x9d shall be interpreted to include either one or two substitutions on that particular nitrogen atom.
As used herein, the term xe2x80x9coxoxe2x80x9d shall refer to the substituent xe2x95x90O.
As used herein, the term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d shall include iodine, bromine, chlorine and fluorine.
As used herein, the term xe2x80x9cmercaptoxe2x80x9d shall refer to the substituent xe2x80x94SH.
As used herein, the term xe2x80x9ccarboxyxe2x80x9d shall refer to the substituent xe2x80x94COOH.
As used herein, the term xe2x80x9ccyanoxe2x80x9d shall refer to the substituent xe2x80x94CN.
As used herein, the term xe2x80x9caminosulfonylxe2x80x9d shall refer to the substituent xe2x80x94SO2NH2.
As used herein, the term xe2x80x9ccarbamoylxe2x80x9d shall refer to the substituent xe2x80x94C(O)NH2.
As used herein, the term xe2x80x9csulfanylxe2x80x9d shall refer to the substituent xe2x80x94Sxe2x80x94.
As used herein, the term xe2x80x9csulfenylxe2x80x9d shall refer to the substituent xe2x80x94S(O)xe2x80x94.
As used herein, the term xe2x80x9csulfonylxe2x80x9d shall refer to the substituent xe2x80x94S(O)2xe2x80x94.
The compounds of formula (I) can be prepared readily according to the following reaction General Synthesis Scheme (in which all variables are as defined before) and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
General Synthesis Scheme 
The most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless noted otherwise.
Abbreviations used in the Examples are as follows:
Reagents are commercially available or are prepared according to procedures in the literature. The physical data given for the compounds exemplified is consistent with the assigned structure of those compounds. 1H NMR spectra were obtained on VARIAN Unity Plus NMR spectrophotometers at 300 or 400 Mhz. Mass spectra were obtained on Micromass Platform II mass spectrometers from Micromass Ltd. Altrincham, UK, using either Atmospheric Chemical Ionization (APCI) or Electrospray Ionization (ESI). Analytical thin layer chromatography (TLC) was used to verify the purity of some intermediates which could not be isolated or which were too unstable for full characterisation, and to follow the progess of reactions. Unless otherwise stated, this was done using silica gel (Merck Silica Gel 60 F254). Unless otherwise stated, column chromatography for the purification of some compounds, used Merck Silica gel 60 (230-400 mesh), and the stated solvent system under pressure.
To a 1-L flask was added a magnetic stir bar, 85 g of sodium sulfate, and 100 mL of water. The mixture was magnetically stirred until all the solids were dissolved. To the resultant aqueous solution was added a solution of 6-aminobenzothiazole (4.96 g, 33.0 mmol) in 50 mL of 1N aqueous hydrochloric acid and 10 mL of ethanol. The mixture was stirred, and chloral (6.0 g, (36 mmol) was added. To the resultant solution was added a solution of hydroxyl amine hydrochloride (7.50 g, 108 mmol) in 30 mL of water. The final mixture was heated with stirring to a gentle boil until all solids dissappeared, and heating was continued for an additional 15 min. The flask was removed from the heat, and the solution was poured onto 500 g of ice. The mixture was stirred as the product precipatated from solution. The precipatate was collected by suction filtration, washed thoroughly with water, filtered, and air dried to provide 6.9 g (94%) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide: 1H NMR (DMSO-d6): xcex4 12.2 (s, 1H), 10.4 (s, 1H), 9.2 (s, 1H), 8.5 (s, 1H), 7.9 (d, 1H), 7.7 (m, 1H), 7.7 (s, 1H); APCIxe2x88x92MS m/z 220 (Mxe2x88x92H)xe2x88x92. To a 1-L 3-neck round bottom flask was placed a magnetic stir bar and 100 ml of concentrated sulfuric acid. The flask was fitted with a thermometer to monitor the temperature of the reaction. The sulfuric acid was heated to 100xc2x0 C., and 10.0 g (45.2 mmol) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide was added slowly. The solution was heated for xcx9c1 h, and the reaction mixture was poured into 750 g of ice and water. The residual reaction mixture in the reaction vessel was washed out with an additional 20 mL of cold water. The aqueous slurry was stirred for about 1 h and filtered. The solid was washed thoroughly with water, filtered, and air dried to yield 4.3 g (46%) of 6-H-1-thia-3,6-diaza-as-indacen-7,8-dione: 1H NMR (DMSO-d6): xcex4 11.1 (s, 1H), 9.2 (s, 1H), 8.2 (d, 1H), 7.0 (d, 1H); APCIxe2x88x92MS m/z 203 (Mxe2x88x92H)xe2x88x92.
To a stirred solution of 1.0 g (6.0 mmol) of chloral hydrate in 25 mL of water was added 7.0 g (22 mmol) of sodium sulfate decahydrate, followed by a solution of 1.18 g (17.0 mmol) of hydroxylamine hydrochloride in 10 mL of water. A solution of 1.0 g (5.4 mmol) of 3-phenoxyaniline in 10 mL of 1.0 N HCl was then added with stirring. The resulting suspension was warmed, and 40 mL of 95% EtOH was added to dissolve the suspension. The solution was refluxed for 0.75 h and then cooled to ambient temperature. The resulting solid was collected by vacuum filtration and air dried to afford 0.95 g (67%) of 2-hydroxyimino-N-(3-phenoxyphenyl)acetamide as a solid: 1H NMR (DMSO-d6): xcex4 6.42 (d, J=8.4 Hz, 1H), 7.06 (d, J=7.9 Hz, 2H), 7.18 (t, J=7.3 Hz, 1H), 7.25-7.50 (m, 5H), 7.64 (s, 1H), 10.29 (s, 1H), 12.21 (s, 1H); APCIxe2x88x92MS: m/z 255 (Mxe2x88x92H)xe2x88x92. A suspension of 0.15 g (0.58 mmol) of 2-hydroxyimino-N-(3-phenoxyphenyl)acetamide in 0.4 mL of BF3 etherate was heated to 85xc2x0 C. for 0.75 h. The mixture was cooled to rt and 10 g of crushed ice was added. The resulting solid was collected by vacuum filtration and subjected to flash chromatography on silica gel (hexane/EtOAc 1.5:1) to afford 6-phenoxy-1H-indole-2,3-dione as a solid (0.018 g, 13%): 1H NMR (DMSO-d6): xcex4 6.44 (d, J=2.0 Hz, 1H), 6.56 (dd, J=2.0, 8.4 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 7.22-7.29 (m, 1H), 7.38-7.46 (m, 2H), 7.52 (d, J=8.4 Hz, 1H), 9.05 (s, 1H); APCIxe2x88x92MS: m/z 255 (M+Na)+.
A solution of 3.78 g (25.0 mmol) of 3-isopropoxy aniline and di-tert-butyl dicarbonate in 25 mL of THF was heated to reflux for 2 h. The solution was cooled to ambient temperature, and solvent was removed in vacuo. The residue was dissolved in 100 mL of EtOAc, and the solution was washed with three 50-mL portions of 0.5 M citric acid and 50 mL of brine. The solution was dried over MgSO4 and removal of solvent in vacuo afforded N-(t-butyloxy-carbonyl)-3-isopropoxyaniline as a white solid (5.75 9, 92%): mp 79-81xc2x0 C.; 1H NMR (DMSO-d6): xcex4 1.21 (d, J=6.0 Hz, 6H), 1.43 (s, 9H), 4.46 (septet, J=6 Hz, 1H), 6.47 (dd, J=2.1, 8.1 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.0-7.1 (m, 2H), 9.23 (s, 1H); APCIxe2x88x92MS: m/z 274 (M+Na)+. To a solution of 2.5 g (10 mmol) of N-(t-butyloxycarbonyl)-3-isopropoxyaniline in 15 mL of dry THF at xe2x88x9278xc2x0 C. was added 15 mL (25 mmol) of 1.7 M t-butyllithium in hexanes. The mixture was stirred at xe2x88x9220xc2x0 C. for 2 h. A solution of 1.84 g (12.5 mmol) of diethyl oxalate in 10 mL of dry THF was added slowly over 5 min, and the mixture was stirred at xe2x88x9220xc2x0 C. for 2 h. The reaction mixture was then poured into 100 mL of 1.0 N HCl and extracted with two 100-mL portions of EtOAc. Solvent was removed in vacuo, and the residue was dissolved in 100 mL of a 1:1 mixture of EtOH and 6 N HCl and heated to reflux for 1 h. The mixture was cooled to ambient temperature and was extracted with four 100-mL portions of EtOAc. The combined extracts were evaporated to dryness to provide crude 4-isopropoxy-1H-indol-2,3-dione, which was dissolved in 10 mL of EtOH containing 0.50 g (2.2 mmol) of 4-sulfonamidophenylhydrazine hydrochloride. The solution was heated to 80xc2x0 C. for 1 h and cooled to ambient temperature. The resulting solid was collected by vacuum filtration and purified by flash chromatography on silica gel (EtOAc/hexane 3:2) to afford the title compound as a yellow solid (0.052 g, 1.4%): mp  greater than 250xc2x0 C.; 1H NMR (DMSO-d6): xcex4 3.35 (d, J=6 Hz, 6H), 4.74 (septet, J=6 Hz, 1H), 6.48 (d, J=7.7 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 7.14-7.2 (m, 3H), 7.47 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 11.01 (s, 1H), 12.79 (s, 1H); APCIxe2x88x92MS: m/z 373 (Mxe2x88x92H)xe2x88x92. Anal. Calcd for C17H18N4O4S: C, 54.53; H, 4.85; N, 14.96; S, 8.56. Found: C, 54.46; H, 4.84; N, 14.90; S, 8.50.
A 2-L three-neck round bottom flask was fitted with an internal thermometer, 250-mL addition funnel, magnetic stir bar and septa. The flask was charged with nitrogen, 200 mL of dry THF, and 6-aminobenzothiazole (15.2 g, 0.100 mol). The mixture was stirred and cooled in a dry ice-acetone bath to an internal temperature of xe2x88x9274xc2x0 C. A solution of tert-butyl hypoclorite (11.0 g, 0.103 mol) in 50 mL of dichloromethane was added over a 15 min period. The resultant solution was stirred for an additional 3 h at dry ice-acetone bath temperature. To the reaction was then added by slow, dropwise addition a solution of ethyl methylthioacetate (13.8 g, 0.103 mol) in 50 mL of dichoromethane. The resultant solution was stirred for an additional 3 h at dry ice-acetone bath temperature. A solution of triethyl amine (25.3 g, 0.250 mol) and 50 ml of dichloromethane was added at dry ice-acetone bath temperature, and the solution was stirred for 0.5 h. The cooling bath was removed, and the reaction was allowed to warm to rt. The reaction was then concentrated to a thick residue. The thick oil was resuspended in 200 mL of ether and 600 mL of 0.25 M hydrochloric acid. The mixture was allowed to stir for 24 h. The resulting solid was filtered from the mixture and triturated with water and ether. The solid was then resuspended in cold MeOH, filtered and dried under vacuum for 16 h to yield 18.7 g (79%) of 8-methylsulfanyl-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one: 1H NMR (DMSO-d6) xcex4 10.8 (s, 1H), 9.2 (s, 1H), 8.0 (d, 1H), 7.1 (d, 1H), 1.8 (s, 3H); APCIxe2x88x92MS m/z 235 (Mxe2x88x92H)xe2x88x92. To a 500-mL erlenmeyer flask was added a stir bar, 8.1 g (0.034 moles) of 8-methylsulfanyl-6,8-dihydro-1-thio-3,6-diaza-as-indacen-7-one and 100 mL of glacial acetic acid. The mixture was stirred until all the starting material had dissolved. The reaction mixture was then diluted with 100 mL of THF. Zinc metal (16 g, 325 mesh) was then added. The heterogeneous mixture was then stirred and heated to 60xc2x0 C. for 2.5 h. The mixture was vacuum filtered through a one half inch pad of celite. The residue on the filter pad was washed with additional THF. The filtrates were combined and concentrated to a wet solid. The solid was triturated with MeOH, filtered and air dried to yield 4.51 g (70%) of 6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one as a free-flowing solid: 1H NMR (DMSO-d6): xcex4 10.5 (s, 1H), 9.1 (s, 1H), 7.9 (d, 1H), 7.0 (d, 1H), 3.6 (s, 2H); APCIxe2x88x92MS m/z 191 (M+H)+.
A solution of 2.66 g (20.0 mmol) of ethyl (methylthio)acetate dissolved in 200 mL of dichloromethane was cooled with stirring to xe2x88x9270xc2x0 C. and 2.7 g (20.0 mmol) of sulfuryl chloride was added. The reaction was stirred for 30 min. at xe2x88x9270xc2x0 C., and a solution of 3.0 g (20 mol) of methyl 4-aminobenzoate and 4.39 (20 mmol) of Proton Sponge(copyright) in 250 mL of dichloromethane was added dropwise over 1 h. The resulting pink slurry was treated with 2.3 g (23 mmol) of TEA in one portion, and the solution was allowed to warm to rt. The solution was washed with three 250-mL portions of water, dried over MgSO4, and concentrated to give an oil. This was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 2.0 g (42% yield) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester: 1H NMR (DMSO-d6): xcex4 1.97 (s, 3H), 3.35 (s, 3H), 4.67 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 7.84 (s, 1H). 7.91 (d, J=8.2 Hz, 1H), 10.97 (s, 1H). A solution of 2.0 g (8.4 mmol) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester in 20 mL of acetic acid was treated with 10 g of zinc powder. The reaction mixture was stirred for 2 h at rt, filtered through celite and concentrated to dryness. The residue was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 1.6 g (99% yield) of 2oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester as a pink solid: 1H NMR (DMSO-d6): xcex4 3.52 (s, 2H), 3.77 (s, 3H), 6.87 (d, J=8.2 Hz, 1H), 7.74 (s, J=1H), 7.80 (d, J=8.2 Hz, 1H), 10.72 (br s, 1H). Conversion to the 3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester (mixture of E and Z isomers) was carried out via Procedure G in 49% yield: 1H NMR (DMSO-d6): xcex4 3.29 Z (s, 6H), 3.31 E (s, 6H), 3.76 Z (s, 3H), 3.76 E (s, 3H), 6.74 Z (d, J=8.1 Hz, 1H), 6.81 E (d. J=8.2 Hz, 1H), 7.47-7.50 Z (m, 1H), 7.50-7.52 E (m, 1H), 7.57 E (dd, J=1.3, 8.2 Hz, 1H), 7.74 Z (s, 1H), 7.89 Z (s, 1H), 7.94 E (s, 1H), 10.33 Z (bs, 1H), 10.43 E (bs, 1H). The title compound was prepared in 41% yield from 3-[(dimethylamino)methylene]oxindole-5-carboxylic acid methyl ester and 4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): xcex4 3.81 (s, 3H), 6.92 (d, J=8.2 Hz, 1H), 7.26 (s, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.2 Hz, 1H). 7.75 (d, J=8.4 Hz, 2H), 8.29 (s, 1H), 8.86 (d, J=12.4 Hz, 1H), 10.80 (d, J=12.4 Hz, 1H), 10.94 (s, 1H); APCIxe2x88x92MS m/z 372 (Mxe2x88x921)xe2x88x92. Anal. Calcd for C17H15N3O5S: C, 54.68, H, 4.05; N, 11.25; S, 8.59. Found C, 54.65, H, 4.12; N, 11.17; S. 8.49.
A solution of 2.3 g (12 mmol) of 3-H-pyrrolo[3,2-f]quinoline-1,2-dione and 2.0 ml (0.06 mol) of hydrazine in 50 ml of DMF and 50 ml of ethanol was stirred at reflux for 2 h. The resulting suspension was allowed to cool to ambient temperature and was then chilled in an ice bath and filtered. The solid was washed with a small volume of ethanol and allowed to air dry to give 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one as an orange solid (1.8 g, 73%): 1H NMR (DMSO-d6): xcex4 7.37 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 4.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 8.71 (dd, J=4.2, 1.6 Hz, 1H), 8.80 (d, J=8.4 Hz, 1H), 9.90 (br d, J=14.7 Hz, 1H), 10.89 (br d, J=14.7 Hz, 1H), 10.95 (br s, 1H); ESIxe2x88x92MS m/z 213 (M+H)+. A solution 1.8 g (8.5 mmol) of 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one in 50 ml of freshly prepared 0.5 M sodium ethoxide solution was stirred at reflux for 3 h. The solution was diluted with 50 ml of water, neutralized with acetic acid, and concentrated on a rotary evaporator until cloudy. The solution was stored in a refrigerator overnight. The solid was filtered off, and the filtrate was extracted with three 80-ml portions of EtOAc. A solution of the solid in MeOH/EtOAc was combined with the extracts. and passed through a short pad of silica gel, eluting with EtOAc. The solution was then concentrated to a small volume on a rotary evaporator, and the resulting suspension was diluted with an equal volume of ethanol, sonicated, and filtered to give 3-H-pyrrolo[3,2-f]quinoline-2-one as a light green solid (0.52 g, 33%); 1H NMR (DMSO-d6): xcex4 3.80 (s, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.4, 4.2 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.70 (dd, J=4.2, 1.6 Hz, 1H), 10.57 (br s, 1H); APCIxe2x88x92MS m/z 183 (Mxe2x88x92H)xe2x88x92.
4,6-Dimethyl-5-hydroxy-1H-indol-2,3-dione was prepared from 3,5-dimethyl-4-hydroxyaniline according to Procedure A: 1H NMR (DMSO-d6): xcex4 2.17 (s, 3H), 2.30 (s, 3H), 6.45 (s, 1H), 8.29 (s, 1H), 10.65 (s, 1H); ESIxe2x88x92MS m/z 190 (Mxe2x88x92H)xe2x88x92. A mixture of 100 mg (0.52 mmol) of 4,6-dimethyl-5-hydroxy-1H-indol-2,3dione and 144 mg (0.57 mmol) of C-(4-hydrazinophenyl)-N-methylmethanesulfonamide hydrochloride in 5 ml of EtOH was heated to 80xc2x0 C. for 1 h. Upon cooling 10 ml of H2O was added and the solid was collected by vacuum filtration and dried in a vacuum oven at 60xc2x0 C. to afford the title compound as a yellow solid (79 mg, 79%); mp 252-255xc2x0 C.; 1H NMR (DMSO-d6): xcex4 2.16 (s, 3H), 2.44 (s, 3H) 2.52 (d, J=4.9 Hz, 3H), 4.25 (s, 2H), 6.47 (s, 1H), 6.84 (q, J=4.9 Hz, 1H), 7.28-7.34 (m, 4H), 7.92 (s, 1H), 10.69 (s, 1H), 12.87 (s, 1H); APCIxe2x88x92MS m/z 411 (M+Na)+. Anal. Calcd for C18H20N4O4S: C, 55.66; H, 5.19; N, 14.42, S, 8.25. Found: C, 55.56; H. 5.21; N, 14.25; S, 8.08.
To a suspension of 1.0 g (5.3 mmol) of 6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one in 7.5 mL of DMF was added 1.38 g (6.80 mmol) of N,N-dimethylformamide-di-t-butyl acetal. The mixture was stirred at ambient temperature for 1 h and diluted with 7.5 mL of Et2O. The resulting precipitate was isolated filtration to afford 8dimethylamino-methylene-6,8dihydro-1-thia-3,6-diaza-as-indacen-7-one as a tan solid (1.0 g, 77%): 1H NMR (DMSO-d6): xcex4 3.33 (bs, 3H), 3.59 (bs, 3H), 6.97 (d, J=8.4, 1H), 7.33 (s, 1H), 7.62 (d, J=8.4, 1H), 9.13 (s,1H), 10.29 (s, 1H); APCIxe2x88x92MS: m/z246 (M+H)+.
To a 250-ml round bottom flask was added a stir bar, 6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one (4.0 g, 0.021 mol), 40 mL of glacial acetic and diethoxymethyl acetate (17.0 g, 0.105 moles). The flask was fitted with a reflux condensor and charged with nitrogen. The reaction was heated to reflux for 8 h. The flask was cooled, the stir bar was removed and the reaction was concentrated to a wet solid. The solid was triturated with a solution of ether and ethanol. The mixture was filtered, the solid was washed with an ethanol-ether solution, and the solid was dried under vacuum to yield 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one: 1H NMR (DMSO-d6): xcex4 10.5 (s, 1H), 9.1 (s, 1H), 7.8 (d, 1H), 7.7 (s, 1H), 7.0 (d, 1H), 4.5 (q, 2H), 1.4 (t, 3H); APCIxe2x88x92MS m/z 245 (Mxe2x88x92H)xe2x88x92.
To a 25 ml round bottom flask was added a stir bar, 246 mg (1.00 mmol) of 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one. 249 (1.00 mmol) of sulfapyridine and 10 ml of ethanol. The flask was fitted with a water-cooled reflux condenser, and the mixture was heated to reflux using an oil bath with stirring for 18 h. The reaction was allowed to cool and was filtered. The precipitate was washed with excess ethanol and dried under vacuum to yield 321 mg (71%) of the title compound: 1H NMR (DMSO-d6): xcex4 11.9 (br s, 1H), 11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 2H), 7.9 (m 3H) 7.8 (m, 1H), 7.6 (d, 2H), 7.2 (d, 1H), 7.2 (d, 1H), 6.9 (t, 1H); C21H15N5O3S2: APCIxe2x88x92MS m/z 450 (M+H)+.
Note: One equivalent of strong acid, e.g., HCl or methanesulfonic acid, is generally required in this reaction. The acid can be supplied as the aniline salt or as a separate component. Similar conditions can be used for condensing anilines with 3-dimethylaminomethylene-, 3-t-butoxymethylene-, and 3-hydroxymethylene-substituted 2,3-dihydro-1H-indol-2-ones.
To 100 mg (0.190 mmol) 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester in 5 mL acetonitrile was added 50 xcexcL (5.6 M in ethanol, 0.28 mmol) of a solution of dimethylamine and 20 xcexcL (0.25 mmol) of pyridine, and the reaction was stirred overnight. The solution was concentrated, and the resulting solid was triturated with EtOAc to give the title compound as a yellow solid (39 mg, 53%): mp greater than 230xc2x0 C.; 1H NMR (DMSO-d6): xcex4 12.71 (s, 1H), 11.22 (s, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.60 (s, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.31 (dd, J=1.7, 8.1 Hz, 1H), 7.23 (s, 2H), 6.93 (d, J=8.0 Hz, 1H), 2.95 (s, 6H); APCIxe2x88x92MS: m/z 386 (mxe2x88x92H). Anal. Calcd for C17H17N5O5S.1/2H2O: C, 51.51; H, 4.58; N, 17.67. Found: C, 51.69; H, 4.25; N, 17.63.
A mixture of 1.0 g (3.6 mmol) of 4-iodo-1H-indole-2,3dione (Snow, et al., Journal of the American Chemical Society 1977, 99, 3734-44), 0.42 g (4.2 mmol) of TEA, 0.06 g (0.27 mmol) of palladium(II) acetate, 0.16 g (0.54 mmol) of tri-o-tolylphosphine and 5.0 g (4.2 mmol) of a 10% solution of 4-vinylphenol in propylene glycol was suspended in 15 mL of dry acetonitrile in a pyrex sealed tube and heated to 100xc2x0 C. for 4 h. The mixture was cooled to rt, quenched with 50 mL of 10% hydrochloric acid and extracted with two 100 mL-portions of EtOAc. The combined extracts were dried over MgSO4 and concentrated to give a brown solid, which was subjected to chromatography on silica gel, eluting with hexane:EtOAc (3:1), to yield 0.125 g (13%) of trans-4-[2-(4-hydroxyphenyl)-vinyl]-1H-indole-2,3-dione as a red solid: 1H NMR (DMSO-d6): xcex4 6.6-7.6 (m, 8H), 7.77 (d, J=16.4 Hz, 1H), 9.85 (bs, 1H), 11.00 (bs, 1H); APCIxe2x88x92MS m/z 264 (Mxe2x88x921)xe2x88x92. Condensation of trans-4-[2-(4-hydroxyphenyl)vinyl]-1H-indole-2,3dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 27% yield as an orange solid: 1H NMR (DMSO-d6): xcex4 6.78 (d, J=7.8 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 7.26 (t, J=7.8 Hz, 1H), ), 7.29 (s, 2H), 7.36 (d, J=16.5 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.53(d, J=8.7 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), ), 7.81 (d, J=8.7 Hz, 2H), 8.03 (d, J=16.5 Hz 1H), 9.78 (s, 1H), 11.17 (s, 1H), 13.02 (s, 1H); APCIxe2x88x92MS m/z433 (Mxe2x88x921)xe2x88x92.
A mixture of 0.028 g (0.64 mmol) of 4-(Nxe2x80x2-{4-[2-(4-hydroxyphenyl)-vinyl]-2-oxo-1,2-dihydro-indol-3-ylidene}-hydrazino)-benzenesulfonamide (Z isomer) and 0.015 g of 10% palladium on charcoal in 60 mL of MeOH:THF (4:1) was subjected to hydrogenation on a Parr apparatus at 50 psi for 1 h. The mixture was filtered through celite, and the filtrate was concentrated to give 0.026 g (93%) of the title compound as a yellow solid: 1H NMR (DMSO-d6): xcex4 2.82 (t, J=8.0 Hz, 2H), 3.23 (t, J=8.0 Hz, 2H), 6.69 (d, J=8.4 Hz, 2H), 6.78 (d, J=7.7 Hz, 1H), 6.89 (d, J=7.7 Hz, 1H), ), 7.07 (d, J=8.4 Hz, 2H), 7.18 (t, J=7.7 Hz, 1H), 7.26 (s, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.8 Hz, 2H), 9.20 (bs, 1H), 11.12 (s, 1H), 13.02 (s, 1H); APCIxe2x88x92MS m/z435 (Mxe2x88x921)xe2x88x92.